The World Health Organization estimates that AIDS has killed more than 25 million people since it was first recognized. In 2007 there were 2.7 million new HIV infections and 2 million HIV-related deaths. Many chronic infections are retroviruses. Anti-retroviral drugs are medications for the treatment of infection by retroviruses such as HIV. When several agents are taken in combination, the approach is known as highly active antiretroviral therapy (HAART). HAART can have serious side-effects. Regimens can be complicated, requiring patients to take several pills at various times during the day. If patients miss doses, drug resistance can develop. Therefore, there remains a need for improved antiviral therapies. In particular, there remains a need for antiviral therapies with reduced toxicity and improved efficacy over existing treatments.
For certain chronic viral infections, the immune system cannot clear the virus from the host even with the aid of therapeutic agents. For example, although HAAT may improve symptoms associated with infection, there is currently no cure for HIV. Toll-like receptors (TLRs) play a role in the pathogenesis of multiple diseases involving both the innate and adaptive immune systems. TLRs in humans recognize different microbial ligands during infection. There are several protein kinases downstream of these adapters, notably the IL-1 receptor-associated kinase (IRAK) family and TBK-1. These activate pathways leading to the activation of the respective transcription factors nuclear factor kappaB (NFκB) and interferon regulatory factor 3 (IRF3), which in turn induce various immune and inflammatory genes.
TLR5 is the receptor for bacterial flagellin monomers. The region of flagellin that TLR5 recognizes is conserved among microbial species and therefore allows TLR5 to detect a wide variety of microbes. TLR5 signals by recruiting the TIR adapter MyD88, leading to the activation of the IKK complex and subsequent activation of the transcription factor NFκB. The activation of TLR5 has been recently reported to be an efficient adjuvant for influenza A vaccines. See, e.g., U.S. Published Patent Application No. 2005/0147627 (flagellin contemplated in vaccine adjuvant). Studies indicate that activating the TLR5 signaling pathway may have other therapeutic applications, not only in its role as a linker adjuvant candidate for vaccines, but also as a dampener of excessive apoptosis in acute radiation syndromes, a characteristic that may be extended for use in degenerative diseases and ischemia reperfusion injury. See, e.g., U.S. Pat. No. 7,638,485. It has been suggested that systemic administration of flagellin may protect against chemicals, bacteria, viruses, and radiation. Vijay-Kumar et al., J Immunol. 2008, 180(12):8280-5. It has also been identified that flagellin reactivates gene expression in certain viruses. See, e.g., Gargano et al., J Virol, (2009), 83(3):1474-82 and Thibault et al., Virology (2009) 389 (1-2): 20-5.